Inherited NBN Mutations and Prostate Cancer Risk and Survival

Abstract

Purpose The purpose of this study was to establish the contribution of four founder alleles of NBN to prostate cancer risk and cancer survival. Materials and Methods Five thousand one hundred eighty-nine men with prostate cancer and 6,152 controls were genotyped for four recurrent variants of NBN (657del5, R215W, I171V, and E185Q). Results The NBN 657del5 mutation was detected in 74 of 5,189 unselected cases and in 35 of 6,152 controls (odds ratio [OR], 2.5; p < 0.001). In carriers of 657del5 deletion, the cancer risk was restricted to men with the GG genotype of the E185Q variant of the same gene. Among men with the GG genotype, the OR associated with 657del5 was 4.4 (95% confidence interval [CI], 2.4 to 8.0). Among men with other E185Q genotypes, the OR associated with 657del5 was 1.4 (95% CI, 0.8 to 2.4) and the interaction was significant (homogeneity p=0.006). After a median follow-up of 109 months, mortality was worse for 657del5 mutation carriers than for non-carriers (hazard ratio [HR], 1.6; p=0.001). The adverse effect of 657del5 on survival was only seen on the background of the GG genotype of E185Q (HR, 1.9; p=0.0004). Conclusion The NBN 657del5 mutation predisposes to poor prognosis prostate cancer. The pathogenicity of this mutation, with regards to both prostate cancer risk and survival, is modified by a missense variant of the same gene (E185Q).

Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland

“…32 There is no organized prostate cancer screening program in Mutation frequencies in cancer-free controls were from our previous studies. [13][14][15][16] these mutations, and therefore the potential to reduce the overall PCa burden will be limited. It is also not known if PSA screening reduces mortality in men with predisposing mutations.…”

“…For BRCA1, CHEK2, NBN and HOXB13, we also used mutation frequencies in the Polish population from previous studies. [13][14][15][16] We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers. Odds ratios were generated from two-by-two tables and statistical significance was assessed with the Fisher exact test.…”

“…We estimated odds ratios for gene and for selected individual mutations. For BRCA1 , CHEK2 , NBN and HOXB13 , we also used mutation frequencies in the Polish population from previous studies 13‐16 . We also compared clinical characteristics of prostate cancers between mutation carriers and noncarriers.…”

Mechanisms of Macrophage Plasticity in the Tumor Environment: Manipulating Activation State to Improve Outcomes

“…During tumorigenesis, genetic mutations can be acquired through exposure to chemical carcinogens (18), radiation (19) or viral infections (20,21). Alternatively, inherited mutations (22,23) or those accumulated during chronic inflammation (24)(25)(26) may also drive carcinogenesis. Cell intrinsic tumor suppressive mechanisms, like DNA repair, senescence or apoptosis (27), often fail to contain tumor cell proliferation, promoting the need for immune-mediated elimination of the aberrant cells.…”

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

“…Heterozygous ATM mutations may also confer a susceptibility to pancreatic cancer (203). Heterozygous carriers of the NBN c.657del5 mutation (which is found in homozygous state in more than 90% of patients with Nijmegen breakage syndrome) who also carry two copies of the NBN polymorphism p.E185Q (GG allele) were shown to be at increased risk for breast and prostate cancers (204,205). These recent studies are the first clear example of genetic modifier effect in a germline cancer syndrome, where the penetrance of a heterozygous allele is "activated" by the presence of an additional modifying polymorphism in the same gene.…”